Plastic containers

ABSTRACT

The present invention provides a method for the commercial presentation of a solution of gadolinium-DOTA that provides certain advantages over the known methods.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to in vivo medical imaging and especiallyto magnetic resonance imaging (MRI). More particularly, the presentinvention relates to a convenient commercial presentation of a solutionof an MRI contrast agent.

DESCRIPTION OF RELATED ART

Metal complexes of lanthanide metals, especially gadolinium, are ofinterest as MRI contrast agents in the field of in vivo medical imaging.MRI contrast agents based on metal complexes of gadolinium have beenreviewed extensively (see e.g. Zhang et al. 2005 Curr Med Chem; 12:751-778 and Aime et al. 2005 Adv Inorg Chem; 57: 173-237).

Gadoteric acid meglumine is a product marketed by Guerbet as Dotarem®.The product is commercially supplied in glass vials and glass pre-filledsyringes(https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204781s001lbl.pdf).The prescribing information instructs that when Dotarem® is to beinjected using plastic disposable syringes, the contrast medium shouldbe drawn into the syringe and used immediately.

Micard et al. (2001 Int J Pharmaceutics; 212: 93-99) discussesrepackaging of Dotarem® into single-use polypropylene syringes and notesthat the solution is stable and sterile according to EuropeanPharmacopoeia up to 90 days in the dark at either 4° C. or at roomtemperature. However, established guidelines advise that apharmaceutical product drawn into a single-use syringe should be usedwithin 24 hours(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003476.pdf).

SUMMARY OF THE INVENTION

In a first aspect the present invention provides a method for providinga solution comprising gadolinium-DOTA wherein said method comprises:

-   -   (i) manufacturing a commercial batch of said solution; and,    -   (ii) dispensing said solution into plastic containers.

In a second aspect the present invention provides a magnetic resonanceimaging (MRI) method comprising:

-   -   (a) providing a plastic container containing a solution        comprising gadolinium-DOTA;    -   (b) administering an imaging effective amount of said solution        to a subject; and,    -   (c) performing MRI on said subject.

Up until the present invention glass containers have been selected forproduct presentations of gadolinium-DOTA, perhaps due to theirrelatively low susceptibility to ingress of oxygen and moisture and tochemical leaching as compared with plastic containers. However, it hasbeen demonstrated herein that plastic containers permit long-termstorage of gadolinium-DOTA without any detrimental effect on productquality due to oxygen or moisture ingress or chemical leaching.Furthermore, the present invention overcomes problems presented by glasscontainers including their relative ease of breakage, the need todispose in special containers, their relatively heavy weight and higheco-impact.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a non-limiting example of a syringe suitable for use in thepresent invention.

FIG. 2 shows non-limiting examples of bottles suitable for use in thepresent invention.

FIGS. 3A and 3B shows non-limiting examples of bags suitable for use inthe present invention (from Sartorius Stedim).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

To more clearly and concisely describe and point out the subject matterof the claimed invention, definitions are provided hereinbelow forspecific terms used throughout the present specification and claims. Anyexemplification of specific terms herein should be considered as anon-limiting example.

The terms “comprising” or “comprises” have their conventional meaningthroughout this application and imply that the agent or composition musthave the essential features or components listed, but that others may bepresent in addition. The term ‘comprising’ includes as a preferredsubset “consisting essentially of” which means that the composition hasthe components listed without other features or components beingpresent.

The term “a solution comprising gadolinium-DOTA” can encompass asolution of gadolinium-DOTA (also can be referred to as “gadotericacid”) prior to formulation as a contrast agent or to the actualformulated contrast agent ready for use. The term “contrast agent” hasits conventional meaning in the field of in vivo medical imaging, andrefers to an agent in a form suitable for mammalian administration,which assists in providing clearer images in the region or organ ofinterest than could be obtained by imaging a subject to whom no contrastagent has been administered. A contrast agent comprising gadolinium-DOTAis an “MRI contrast agent”, suitable for mammalian administration, whichshortens the T1 and/or T2 relaxation time of the relevant nuclei (e.g.¹H for ¹H NMR) in the region of interest for imaging within a subject.

In one embodiment of the method of the invention said gadolinium-DOTA isthe meglumine salt of gadolinium-DOTA, also commonly referred to asGd-DOTA meglumine or gadoterate meglumine.

In one embodiment the solution comprising gadolinium-DOTA furthercomprises a mol/mol amount of free DOTA between 0.002% and 0.4%, inanother embodiment between 0.02 and 0.3% of free DOTA, in anotherembodiment between 0.025 and 0.25 mol/mol % of free DOTA.

The macrocyclic chelator DOTA and its metal complexes in biomedicalimaging have been described by Stasiuk and Long (2013 Chem Comm; 49:2732-2746) and has the following structure:

DOTA is commercially available from a range of suppliers and can also besynthesised by the method of Desreux (1980 Inorg Chem; 19: 1319-1324).Further details on macrocyclic chelator syntheses are given by Kotel etal. (Chapter 3 pages 83-155 in “The Chemistry of Contrast Agents inMedical Magnetic Resonance Imaging; Wiley 2^(nd) Edition 2013: A.Merbach, L. Helm & E. Toth, Eds).

Meglumine (N-methylglucamine) is commercially available from a range ofsuppliers. Pharmaceutical grade material is generally used.

The complexation of lanthanides such as gadolinium by macrocyclicchelators is a multistep process that results in a thermodynamicallystable metal complex. Non-limiting examples of gadolinium-DOTA solutionsas well as methods to prepare gadolinium-DOTA and its meglumine salt aredescribed in WO 2009/103744, WO 2016/083597, WO 2016/083600 and WO2016/083605, the contents of which are hereby incorporated by reference.US 2012/0082624 A1 discloses a similar process to WO 2009/103744, exceptthat the pharmaceutical formulation is obtained in powder form.

By the phrase “in a form suitable for mammalian administration” is meanta composition which is sterile, pyrogen-free, lacks compounds whichproduce toxic or adverse effects, and is formulated at a biocompatiblepH (approximately pH 4.0 to 10.5) in a biocompatible carrier. Suchcompositions lack particulates which could risk causing emboli in vivo,and are formulated so that precipitation does not occur on contact withbiological fluids (e.g. blood). Such compositions also contain onlybiologically compatible excipients, and are preferably isotonic.

By the term “biocompatible carrier” is meant a fluid, especially aliquid, such that the composition is physiologically tolerable, i.e. canbe administered to the mammalian body without toxicity or unduediscomfort. The biocompatible carrier is suitably an injectable carrierliquid such as sterile, pyrogen-free water for injection; an aqueoussolution such as saline (which may advantageously be balanced so thatthe final product for injection is isotonic); an aqueous buffer solutioncomprising a biocompatible buffering agent (e.g. phosphate buffer); anaqueous solution of one or more tonicity-adjusting substances (e.g.salts of plasma cations with biocompatible counterions), sugars (e.g.glucose or sucrose), sugar alcohols (e.g. sorbitol or mannitol), glycols(e.g. glycerol), or other non-ionic polyol materials (e.g.polyethyleneglycols, propylene glycols and the like). Preferably thebiocompatible carrier is pyrogen-free water for injection (WFI),isotonic saline or phosphate buffer.

Production of the solution comprising gadolinium-DOTA is suitablycarried out under aseptic manufacture conditions. The phrase “asepticmanufacture” refers to carrying out the relevant process steps underaseptic manufacture, i.e. apyrogenic conditions, e.g. in a clean-roomenvironment, including terminal sterilisation. The term “sterilisation”takes its conventional meaning, and refers to a process of destructionof micro-organisms, to obtain a sterile, pyrogen-free composition. Thephrase “terminal sterilisation” has its conventional meaning, and refersto carrying out the preceding steps to GMP (Good ManufacturingPractice), but carrying out the sterilisation step as late as possiblein the overall process. The components and reagents can be sterilised bymethods known in the art, including: sterile filtration, terminalsterilisation using e.g. gamma-irradiation, autoclaving, dry heat orchemical treatment (e.g. with ethylene oxide) or combinations thereof.The term “autoclaving” has its' conventional meaning, and refers to oneparticular method of sterilisation which uses superheated steam tosterilise. Autoclaving and other sterilisation methods are described inAchieving Sterility in Medical and Pharmaceutical Products, N. Halls(CRC Press, 1994).

The term “commercial batch” refers to a relatively large quantity of thesolution comprising gadolinium-DOTA to fulfil demand for commercialproduct offerings comprising said solution. In one embodiment acommercial batch may be regarded as a batch having a volume of around400 L or greater, up to around 1500 L. For example, in certainembodiments said commercial batch has a volume around 600 L or greater,around 700 L or greater, around 800 L or greater, around 900 L orgreater, around 1000 L or greater, or between 1000-1500 L, for example1400 L.

The term “plastic containers” in the context of the present invention isintended to refer to containers made of pharmaceutical grade plasticsuitable for the safe and efficient storage, transport and handling ofthe gadolinium-DOTA solution. Such containers can be readily obtainedcommercially. In certain embodiments of the invention said plasticcontainers are made from pharmaceutical-grade polypropylene. In otherembodiments of the invention said plastic containers are made frompharmaceutical-grade cyclic olefin. Examples of particular plasticcontainers suitable for the present invention include plastic syringes,plastic containers and plastic bags. Where the plastic container is asyringe or a bottle it is suitable for containing one or more imagingeffective doses of the solution where the solution is the finalformulated solution of gadolinium DOTA suitable for use as an MRI agent.

Non-limiting examples of suitable syringes include those having a 10 mL,15 mL or 20 mL volume. A non-limiting example of a syringe suitable forthe present invention is illustrated in FIG. 1. The followingcharacteristics are present in certain embodiments of plastic syringessuitable for the present invention:

-   -   Durable, medical-grade pharmaceutical polymer construction    -   Dispose in regular waste disposal    -   Are fully re-cyclable    -   Cost saving    -   Lighter weight

In one embodiment said syringe is made from pharmaceutical-grade cyclicolefin. Cyclic olefin has good transparency, which facilitates visuallyverifying the contents.

Non-limiting example of suitable bottles are those having volumesbetween 50-500 mL, e.g. 50 mL, 100 mL, 150 mL, 500 mL or 1000 mL. In oneembodiment said bottle can be of the type described in WO 00/03920. Incertain embodiments said bottle may be of a type as described in any ofU.S. Pat. No. 6,659,296, WO2013041593, U.S. Pat. No. 9,815,601, EP2790636 B1, U.S. Pat. No. 9,682,015, WO2014106002 and WO2016014406. Inone embodiment said bottle can be the Pluspak™ available from GEHealthcare of the type illustrated in FIG. 2. Pluspak™ is apolypropylene based bottle having the following characteristics:

-   -   Durable, medical-grade pharmaceutical polymer construction    -   Easy twist-off cap without metal Latex-free stopper    -   Latex-free stopper    -   Dispose in regular waste disposal    -   Fully re-cyclable    -   Cost saving    -   Compact size, 75% lighter weight (100 ml)    -   Average of 41% lower eco-impact than glass during whole        lifecycle (vs. GEHC glass bottles)

Where the plastic container is a bag it is in one embodiment a flexibleplastic bag suitable for the transport and storage of thegadolinium-DOTA solution. Suitable plastic bags are commerciallyavailable and non-limiting examples of these are illustrated in FIGS. 3Aand 3B. In one embodiment the plastic bag of the invention has a 50-1000L volume.

Particular properties of a suitable bag include:

-   -   Pharmacopoeia compliance.    -   Enables transport and storage of the gadolinium-DOTA solution.    -   Is more Eco-friendly vs. steel drums.    -   The bags are flexible with respect to filling volumes.

In certain embodiments of the invention said method further comprisesthe step (iii) of storing said solution dispensed into said plasticcontainers. The term “storing” takes its conventional meaning of placingor leaving in a suitably secure location for preservation with theintention to use at a later date. In one embodiment of the method of theinvention said storing is for more than 90 days, for example for up to36 months. In one embodiment of the method of the invention said storingis at temperatures up to 30° C. The present inventors have demonstratedthat storing is possible over a wide range of temperatures and for along shelf life without any impact on the quality of the gadolinium-DOTAsolution.

Both oxygen content and free Gd were tested by for up to 24 months forthe drug product stored at both 25° C./40% RH (RH=relative humidity) and30° C./75% RH and up to 6 months at 40° C./75% RH and 40° C./20% RH.Furthermore, the product was tested for oxygen and free Gd after bothconfirmatory photostability testing according to ICH Q1B (which may beviewed at this link:http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1B/Step4/Q1B_Guideline.pdf)and temperature cycling from −20° C. to 60° C. All results show thatfree Gd has not been detected indicating stability of the product underthe various storage conditions. ICH Q1E guideline (which may be viewedat this link:http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1E/Step4/Q1E_Guideline.pdf)allows extrapolation up to a 30 months shelf life at the long termstorage condition of 25° C./40% RH. Therefore, the results obtained bythe present inventors demonstrate that gadoterate meglumine solution canbe effectively stored in semi-permeable containers such as polymer PFSand PP bottles during long term storage at 25° C./40% RH up to 30months. This is despite some of the harsh conditions to which theproduct was exposed and the fact that these containers permit ingress ofoxygen resulting in raised oxygen levels in the containers.

In certain embodiments of the method of the invention said dispensingincludes carrying out an overfill to counteract any water loss fromplastic containers over time in order to maintain product quality. Inone embodiment said overfill is 1-5% of the final desired volume.

In certain embodiments of the method of the invention nitrogen is notused as an excipient in the plastic container headspace. The presentinventors have demonstrated that oxygen in the headspace of the plasticcontainers does not have a material impact on the quality of theproduct.

The term “magnetic resonance imaging” herein takes its ordinary meaningin the art, that is a form of medical imaging that measures the responseof the atomic nuclei of body tissues to high-frequency radio waves whenplaced in a strong magnetic field, and that produces images of theinternal organs.

The term “an imaging effective amount” refers to an amount of thegadolinium-DOTA active agent sufficient to produce useful images usingMRI following administration to a subject. For adult and paediatricpatients (2 years and older), the recommended dose of thegadolinium-DOTA product Dotarem® is 0.2 mL/kg (0.1 mmol/kg) body weightadministered as an intravenous bolus injection, manually or by powerinjector, at a flow rate of approximately 2 mL/second for adults and 1-2mL/second for pediatric patients. Additional information can be found athttp://www.guerbet-us.com/products/dotarem.html.

By the term “subject” is meant a mammal in vivo, preferably the intactmammalian body in vivo, and more preferably a living human subject.

As with other in vivo imaging agents, the contrast agent is designed tohave minimal pharmacological effect on the mammalian subject to beimaged. Preferably, the contrast agent can be administered to themammalian body in a minimally invasive manner, i.e. without asubstantial health risk to the subject when carried out underprofessional medical expertise. Such minimally invasive administrationis preferably intravenous administration into a peripheral vein of saidsubject, without the need for local or general anaesthetic.

This written description uses examples to disclose the invention,including the best mode, and also to enable any person skilled in theart to practice the invention, including making and using any devices orsystems and performing any incorporated methods. The patentable scope ofthe invention is defined by the claims, and may include other examplesthat occur to those skilled in the art. Such other examples are intendedto be within the scope of the claims if they have structural elementsthat do not differ from the literal language of the claims, or if theyinclude equivalent structural elements with insubstantial differencesfrom the literal languages of the claims. All patents and patentapplications mentioned in the text are hereby incorporated by referencein their entireties, as if they were individually incorporated.

BRIEF DESCRIPTION OF THE EXAMPLES

Example 1 describes preparation and storage of a gadoteric acid solutionand measurements of stability over time and under different storageconditions.

LIST OF ABBREVIATIONS USED IN THE EXAMPLES

-   GC-TCD gas chromatography thermal conductivity detector-   ICH International Conference on Harmonisation-   ND not detected-   PFS polymer pre-filled syringes-   PP polypropylene-   RH relative humidity

Example 1: Stability of Solution Comprising Gadolinium-DOTA in PlasticContainers Under Various Storage Conditions

A gadoteric acid solution suitable for injection (referred to as DrugProduct below) was prepared in three commercial scale 400 L batches.Each batch was filled into glass, PFS and PP bottles and autoclavedprior to storage.

In order to cover climatic zone I, II and IV Drug Product samples werestored long term up 24 months at both 25° C./40% RH and 30° C./75% RHand at the accelerated storage conditions of both 40° C./75% RH and 40°C./20% RH up to 6 months. Furthermore, confirmatory photostabilitytesting according to ICH Q1B has been performed and temperature cyclingfrom −20° C. to 60° C. has been performed.

PFS data is detailed below to demonstrate both Free Gd and level ofoxygen content. Satisfactory results below detection limit for Free Gd(limit of detection=NMT 3 μL/mL) were also obtained for PP bottles up to24 months at 25° C./40% RH and 30° C./75% RH and for bags up to 6 monthsat 25° C./40% RH, 30° C./75% RH and 40° C./20% RH. All results for theDrug Product met specification for all containers mentioned above.

Measured oxygen content increased up to 20% during storage long termstorage at 25° C./40% RH and 30° C./75% RH, the same trend is seen forsamples stored at the accelerated storage condition of 40° C./75% RH and40° C./20% RH up to 6 months. The increase in oxygen content was notshown to impact the stability of the drug product throughout shelf life.No free Gd was detected during stability testing. See Table 1 below fora summary of the various batches of product filled in PFS stored andtested and an index to the results for each batch.

TABLE 1 Index to stability result tables for 20 mL syringes with fillvolumes 10, 15 and 20 mL Fill Results 1volume Batch Storage conditionpresented (mL) number ° C. % RH Position Light in 10 1 25 40 On-sideDark Table 2 1 30 75 On-side Dark Table 3 1 40 20 On-side Dark Table 4 140 75 On-side Dark Table 5 1 25 Ambient On-side Light Table 6 15 2 25 40On-side Dark Table 7 2 30 75 On-side Dark Table 8 2 40 20 On-side DarkTable 9 2 40 75 On-side Dark Table 10 10 1 −20 to Ambient On-side DarkTable 11 60 20 3 25 40 On-side Dark Table 12 3 30 75 On-side Dark Table13 3 40 20 On-side Dark Table 14 3 40 75 On-side Dark Table 15

TABLE 2 Stability results on batch 1 stored at 25° C./40%RH/On-side/Dark (20 mL syringe, 10 mL fill volume) Accep- tance Samplingpoint (months) Test criteria 0 3 6 9 12 18 24 Oxygen in Report 16.6,19.1, 20.0, 19.9, 20.1, 20.1 — headspace value, % 17.5, 18.8, 20.2,20.0, 20.1, 20.3 by GC- 16.5 19.1 19.9 20.1 20.2 19.9 TCD Free Gd Not NDND ND ND ND ND — by colour detected limit test — Testing not required as30° C./75% RH results cover this sampling point

TABLE 3 Stability results on batch 1 stored at 30° C./75%RH/On-side/Dark (20 mL syringe, 10 mL fill volume) Accep- tance Samplingpoint (months) Test criteria 0 3 6 9 12 18 24 Oxygen in Report 16.6,18.3, 19.6, 19.7, 19.9, 19.6, 20.1, headspace value, % 17.5, 18.0, 19.8,19.6, 20.3, 19.7, 20.2, by GC- 16.5 18.4 19.8 19.7 20.0 19.8 20.1 TCDFree Gd Not ND ND ND ND ND ND ND by colour detected limit test

TABLE 4 Stability results on batch 1 stored at 40° C./20%RH/On-side/Dark (20 mL syringe, 10 mL fill volume) Acceptance Samplingpoint (months) Test criteria 0 1 3 6 Oxygen in Report 16.6, 16.7, 18.7,19.0, headspace value, % 17.5, 16.3, 17.8, 19.5, by GC-TCD 16.5 17.518.2 19.4 Free Gd by Not ND ND ND ND colour detected limit test

TABLE 5 Stability results on batch 1 stored at 40° C./75%RH/On-side/Dark (20 mL syringe, 10 mL fill volume) Acceptance Samplingpoint (months) Test criteria 0 6 Oxygen in Report 16.6, 17.5, 19.0,19.0, headspace value, % 16.5 18.7 by GC-TCD Free Gd by Not ND ND colourdetected limit test

TABLE 6 Stability results on batch 1 stored at 25 °C./Ambient/On- side(20 mL syringe, 10 mL fill volume) Photo stability study Accep- Samplingpoint (days) tance Dark Test criteria 0¹⁾ 3²⁾ 7³⁾ 23⁴⁾ control Oxygen inReport 18.3, 18.6, 19.0, 16.0, 19.9, headspace value, % 18.0, 19.4,18.9, 15.6, 19.2, by GC-TCD 18.4 18.7 19.0 15.8 19.8 Free Gd Not ND NDND ND ND by colour detected limit test — means that the test has notbeen performed at the specified sampling point, ND: Not detected, LT:Less than, NLT: Not less than, NMT: Not more than ¹⁾Zero point photostability: SN1506.013, data from 3 months sampling point ²⁾Lux: 0.358mill lux h, UVA 30.5 Wh/m² ³⁾Lux: 0.832 mill lux h, UVA 71 Wh/m² ⁴⁾Lux:1.64 mill lux h, UVA 206.1 Wh/m² 5) Reported according to method at thetime of testing

TABLE 7 Stability results on batch 2 stored at 25° C./40%RH/On-side/Dark (20 mL syringe, 15 mL fill volume) Accep- tance Samplingpoint (months) Test criteria 0 3 6 9 12 18 24 Oxygen in Report 15.9,19.8, 20.1, 20.2, 20.1, 20.6, — headspace value, % 15.6, 19.0, 20.1,20.3, 20.2, 20.2, by GC- 16.4 19.1 19.8 20.1 20.2 20.1 TCD Free Gd NotND ND ND ND ND ND — by colour detected limit test — Testing not requiredas 30° C./75% RH results cover this sampling point

TABLE 8 Stability results on batch 2 stored at 30° C./75%RH/On-side/Dark (20 mL syringe, 15 mL fill volume) Accep- tance Samplingpoint (months) Test criteria 0 3 6 9 12 18 24 Oxygen in Report 15.9,18.3, 19.6, 19.7, 19.8, 20.2, 19.8 headspace value, % 15.6, 18.1, 19.8,19.6, 19.9, 20.2, 20.3 by GC- 16.4 18.7 19.5 19.8 20.0 19.9 19.7 TCDFree Gd Not ND ND ND ND ND ND ND by colour detected limit test

TABLE 9 Stability results on batch 2 stored at 40° C./20%RH/On-side/Dark (20 mL syringe, 15 mL fill volume) Acceptance Samplingpoint (months) Test criteria 0 1 3 6 Oxygen in Report 15.9, 16.8, 18.8,19.5, headspace value, % 15.6, 17.1, 18.2, 19.4, by GC-TCD 16.4 17.718.2 19.6 Free Gd by Not ND ND ND ND colour detected limit test

TABLE 10 Stability results on batch 2 stored at 40° C./75%RH/On-side/Dark (20 mL syringe, 15 mL fill volume) Acceptance Samplingpoint (months) Test criteria 0 3 6 Oxygen Report 15.9, 17.9, 19.2, inheadspace value, % 15.6, 17.8, 19.4, by GC-TCD 16.4 17.9 19.2 Free Gd byNot ND ND ND colour detected limit test

TABLE 11 Stability results on batch 1 stored at −20° C. to 60°C./Ambient/On-side/Dark (20 mL syringe, 10 mL fill volume). Temperaturecycling study Acceptance Sampling point (days) Test criteria 0¹⁾ 12Oxygen in Report 18.3, 18.0, 17.1, 17.0, headspace value, % 18.4 17.3 byGC-TCD Free Gd by Not ND ND colour detected limit test

TABLE 12 Stability results on batch 12907764 stored at 25° C./40%RH/On-side/Dark (20 mL syringe, 20 mL fill volume) Accep- tance Samplingpoint (months) Test criteria 0 3 6 9 12 18 24 Oxygen in Report 12.7,19.3, 19.5, 19.9, 20.1, 20.3, — headspace value, % 12.8, 19.3, 19.6,20.0, 20.3, 20.1, by GC-TCD 13.5 19.1 19.5 20.0 20.2 20.4 Free Gd Not NDND ND ND ND ND — by colour detected limit test — Testing not required as30° C./75% RH results cover this sampling point

TABLE 13 Stability results on batch 3 stored at 30° C./75%RH/On-side/Dark (20 mL syringe, 20 mL fill volume) Accep- tance Samplingpoint (months) Test criteria 0 3 6 9 12 18 24 Oxygen in Report 12.7,18.7, 19.5, 19.8, 19.8, 20.0, 21.0, headspace value, % 12.8, 18.5, 19.6,19.7, 20.1, 19.9, 21.0, by GC- 13.5 18.2 19.4 19.8 19.7 19.8 21.2 TCDFree Gd Not ND ND ND ND ND ND ND by colour detected limit test

TABLE 14 Stability results on batch 3 stored at 40° C./20%RH/On-side/Dark (20 mL syringe, 20 mL fill volume) Acceptance Samplingpoint (months) Test criteria 0 1 3 6 Oxygen in Report 12.7, 16.6, 18.2,19.5, headspace value, % 12.8, 17.1, 18.1, 19.8, by GC-TCD 13.5 17.018.5 19.3 Free Gd by Not ND ND ND ND colour detected limit test

TABLE 15 Stability results on batch 3 stored at 40° C./75%RH/On-side/Dark (20 mL syringe, 20 mL volume) Acceptance Sampling point(months) Test criteria 0 6 Oxygen in Report 12.7, 12.8, 19.4, 19.6,headspace value, % 13.5 19.5 by GC-TCD Free Gd by Not ND ND colourdetected limit test

The invention claimed is:
 1. A method for providing a gadolinium-DOTAsolution in a syringe wherein said method comprises: (i) manufacturing abatch of said gadolinium-DOTA solution; and, (ii) dispensing saidgadolinium-DOTA solution into a pharmaceutical-grade cyclic olefinplastic syringe; wherein said syringe comprises oxygen in the headspaceof the syringe and is sufficiently transparent to permit visualverification of the contents of the syringe, the gadolinium-DOTA withinthe oxygen-containing syringe being stable for up to 36 months.
 2. Themethod as defined in claim 1 wherein said gadolinium-DOTA is themeglumine salt of gadolinium-DOTA.
 3. The method as defined in claim 1wherein said solution comprising gadolinium-DOTA further comprises amol/mol amount of free DOTA between 0.002% and 0.4%.
 4. The method asdefined in claim 1 wherein said syringe has a 10 mL volume.
 5. Themethod as defined in claim 1 wherein said syringe has a 15 mL volume. 6.The method as defined in claim 1 wherein said syringe has a 20 mLvolume.
 7. The method as defined in claim 1 wherein said plasticcontainer is a bottle.
 8. The method as defined in claim 7 wherein saidbottle has a 50 mL volume.
 9. The method as defined in claim 7 whereinsaid bottle has a 100 mL volume.
 10. The method as defined in claim 1wherein said plastic container is a bag.
 11. The method as defined inclaim 10 wherein said bag has a 50-1000 L volume.
 12. The method asdefined in claim 1 wherein said batch is a 400-1400 L batch.
 13. Themethod as defined in claim 1 wherein said method further comprises thestep (iii) of storing said solution dispensed into said plasticcontainers.
 14. The method as defined in claim 13 wherein said storingis at temperatures up to 30° C.
 15. The method as defined in claim 1wherein said dispensing includes an overfill.
 16. The method as definedin claim 15 wherein said overfill is 1-5% of the final desired volume.17. The method as defined in claim 1 wherein nitrogen is not used as anexcipient in the plastic container headspace.
 18. A magnetic resonanceimaging (MRI) method comprising: (a) manufacturing a batch ofgadolinium-DOTA solution and, dispensing said gadolinium-DOTA solutioninto a pharmaceutical-grade cyclic olefin plastic syringe, wherein saidsyringe comprises oxygen in the headspace of the syringe and issufficiently transparent to permit visual verification of the contentsof the syringe, the gadolinium-DOTA within the oxygen-containing syringebeing stable for up to 36 months; (b) administering an imaging effectiveamount of said solution to a subject; and, (c) performing MRI on saidsubject.